There is a strong association between aging and the development of cancer; however, precise mechanisms remain largely unknown. Testicular Orphan Receptor 4 (TR4) belongs to the nuclear receptor superfamily, and knockout of TR4 (TR4-/-) results in premature aging in mice and early onset of G2/M growth arrest in the mouse embryonic fibroblasts, where TR4-/- cells acquire genome instability. Further mechanistic studies suggest that TR4 is able to mediate cellular response to DNA-damage signals by blocking reactive oxygen species and promoting DNA repair capacity, both of which counteract tumor promotion. A few surviving aged TR4-/- mice developed abnormal proliferative lesions of prostatic hyperplasia and/or dysplasia at the age of 17 months while wild type littermates retained an intact prostatic structure. Tissue Microarray Analysis of TR4 profiles from human prostate samples found TR4 expressions were increased and shifted from the nucleus to cytoplasm proportionally with the progression of disease, then declined and appeared only in the cytoplasm of specimens of metastases in bone. Genomic sequence analyses of TR4 gene from high-grade prostate cancer specimens where TR4 protein is located in the cytoplasm showed TR4 gene is mutated at the nuclear translocation signal (TR4m/nsl), in the exon 5, and this TR4m/nsl loses both nuclear translocation and transactivating ability. We hypothesize that TR4 is an anti-cancer barrier that is activated in the early stage of tumorigenesis to guard against genetic instability. Dysfunction of TR4 caused by a mutation, which disrupts its nuclear translocation, contributes to tumor progression; thereby the TR4 expression profile is a new prognostic marker for predicting disease behavior outcomes. Four aims are proposed. AIM 1: To screen TR4 gene mutation in human prostate cancer specimens and correlate with TR4 protein aberrations. AIM 2: Characterization of TR4m/nls behavior and its contribution to prostate cancer development and progression. AIM 3: To elucidate the underlying mechanisms of how TR4 suppresses prostate cancer development and progression, and to identify the molecules which are responsible. AIM 4: To correlate TR4 expression levels/patterns with clinical outcomes in prostate cancer patients. Our goals are to understand the tumor suppressive roles of TR4 in maintaining prostate homeostasis and preventing malignant transformation as well as to identify TR4 as a novel biomarker for prostate cancer, which will lead to more accurate diagnoses and better prognosis by utilizing TR4. PUBLIC HEALTH RELEVANCE: Our proposal will study the functions of a newly identified prostate tumor suppressor gene, TR4 orphan receptor, and determine whether TR4 is a novel biomarker for prostate cancer. Our study will lead to more accurate diagnosis and better prognosis for prostate cancer, and facilitate genetic or pharmacological intervention to slow this disease by utilizing TR4.